tbuckley/cabot-search huggingface dataset:
Human anti-smallpox long-lived memory B cells are defined by dynamic interactions in the splenic niche and long-lasting germinal center imprinting
Authors: Pascal Chappert, François Huetz, Marie-Alix Espinasse, Fabrice Chatonnet, Louise Pannetier, Lucie Da Silva, Clara Goetz, Jérome Mégret, Aurélien Sokal, Etienne Crickx, Ivan Nemazanyy, Vincent Jung, Chiara Guerrera, Sébastien Storck, Matthieu Mahévas, Antonio Cosma, Patrick Revy, Thierry Fest, Claude-Agnès Reynaud, Jean-Claude Weill
Journal: Immunity (2022)
Striatal dopamine explains novelty-induced behavioral dynamics and individual variability in threat prediction
Authors: Korleki Akiti, Iku Tsutsui-Kimura, Yudi Xie, Alexander Mathis, Jeffrey E. Markowitz, Rockwell Anyoha, Sandeep Robert Datta, Mackenzie Weygandt Mathis, Naoshige Uchida, Mitsuko Watabe-Uchida
Journal: Neuron (2022)

Animals both explore and avoid novel objects in the environment, but the neural mechanisms that underlie these behaviors and their dynamics remain uncharacterized. Here, we used multi-point tracking (DeepLabCut) and behavioral segmentation (MoSeq) to characterize the behavior of mice freely interacting with a novel object. Novelty elicits a characteristic sequence of behavior, starting with investigatory approach and culminating in object engagement or avoidance. Dopamine in the tail of the striatum (TS) suppresses engagement, and dopamine responses were predictive of individual variability in behavior. Behavioral dynamics and individual variability are explained by a reinforcement-learning (RL) model of threat prediction in which behavior arises from a novelty-induced initial threat prediction (akin to "shaping bonus") and a threat prediction that is learned through dopamine-mediated threat prediction errors. These results uncover an algorithmic similarity between reward- and threat-related dopamine sub-systems.
Anandamide and other N-acylethanolamines: A class of signaling lipids with therapeutic opportunities
Authors: Elliot D. Mock, Berend Gagestein, Mario van der Stelt
Journal: Progress in Lipid Research (2022)

N-acylethanolamines (NAEs), including N-palmitoylethanolamine (PEA), N-oleoylethanolamine (OEA), N-arachidonoylethanolamine (AEA, anandamide), N-docosahexaenoylethanolamine (DHEA, synaptamide) and their oxygenated metabolites are a lipid messenger family with numerous functions in health and disease, including inflammation, anxiety and energy metabolism. The NAEs exert their signaling role through activation of various G protein-coupled receptors (cannabinoid CB1 and CB2 receptors, GPR55, GPR110, GPR119), ion channels (TRPV1) and nuclear receptors (PPAR-α and PPAR-γ) in the brain and periphery. The biological role of the oxygenated NAEs, such as prostamides, hydroxylated anandamide and DHEA derivatives, are less studied. Evidence is accumulating that NAEs and their oxidative metabolites may be aberrantly regulated or are associated with disease severity in obesity, metabolic syndrome, cancer, neuroinflammation and liver cirrhosis. Here, we comprehensively review NAE biosynthesis and degradation, their metabolism by lipoxygenases, cyclooxygenases and cytochrome P450s and the biological functions of these signaling lipids. We discuss the latest findings and therapeutic potential of modulating endogenous NAE levels by inhibition of their degradation, which is currently under clinical evaluation for neuropsychiatric disorders. We also highlight NAE biosynthesis inhibition as an emerging topic with therapeutic opportunities in endocannabinoid and NAE signaling.
Drug-Resistant Ventricular Tachycardia of 62 Days' Duration
Authors: Thaddeus R. Kilpatrick
Journal: JAMA (1966)

In a case of ventricular tachycardia of 62 days' duration, a 66-year-old man was successfully treated by direct-current countershock. It is believed that this case represents the longest duration on record of ventricular tachycardia in which the patient was successfully treated and able to resume normal activity. The ease with which the rhythm was corrected by direct-current countershock after unsuccessful drug therapy was indeed impressive. Three attacks of ventricular tachycardia during the subsequent nine months were also terminated successfully by direct-current countershock.
Omission in Title
Journal: JAMA Network Open (2022)

Fidel Rubagumya, MD; Wilma M. Hopman, MA; Bishal Gyawali, MD; Deborah Mukherji, MD; Nazik Hammad, MBBS; C. S. Pramesh, MBBS; Mykola Zubaryev, MD; Alexandru Eniu, MD; Audrey T. Tsunoda, MD; Tezer Kutluk, MD; Ajay Aggarwal, MD; Richard Sullivan, MD; Christopher M. Booth, MD
Effectiveness of Standard Sequential Bilateral Repetitive Transcranial Magnetic Stimulation vs Bilateral Theta Burst Stimulation in Older Adults With Depression
Authors: Daniel M. Blumberger, Benoit H. Mulsant, Kevin E. Thorpe, Shawn M. McClintock, Gerasimos N. Konstantinou, Hyewon H. Lee, Sean M. Nestor, Yoshihiro Noda, Tarek K. Rajji, Alisson P. Trevizol, Fidel Vila-Rodriguez, Zafiris J. Daskalakis, Jonathan Downar
Journal: JAMA Psychiatry (2022)

Treatment-resistant depression (TRD) is common in older adults. Bilateral repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex for 48 minutes has demonstrated efficacy in TRD. Theta burst stimulation (TBS), a newer form of rTMS, can also be delivered bilaterally using left intermittent TBS and right continuous TBS for only 4 minutes.To establish the effectiveness and tolerability of TBS compared with standard rTMS in older adults with TRD.In this randomized noninferiority trial with open treatment and blinded assessors, recruitment occurred between December 2016 and March 2020. The trial was conducted at the Centre for Addiction and Mental Health in Toronto, Ontario, Canada and included outpatients 60 years and older with a diagnosis of depression, moderate severity, and nonresponse to 1 or more antidepressant trial of adequate dosage and duration or intolerance of 2 or more trials.Participants were randomized to receive a course of 4 to 6 weeks of either bilateral standard rTMS or TBS.The primary outcome measure was change in Montgomery-Åsberg Depression Rating Scale; secondary outcome measures included the 17-item Hamilton Rating Scale for Depression, Quick Inventory of Depressive Symptomatology (16-item) (self-report), and dropout rates. A noninferiority margin of 2.75 points was used for the primary outcome. All participants who attained the primary completion point of 4 weeks were analyzed.A total of 87 participants (mean [SD] age, 67.1 [6.7] years; 47 [54.0%] female) were randomized to standard bilateral rTMS and 85 (mean [SD] age, 66.3 [5.3] years; 45 [52.9%] female) to TBS, of whom 85 (98%) and 79 (93%) were assessed for the primary outcome, respectively, whereas tolerability was assessed in all randomized participants. In the rTMS group, 4 (4.6%) were American Indian, reported other, or preferred not to answer; 5 (5.8%) were Asian; and 78 (89.7%) were White. In the TBS group, 6 (7.1%) were Asian, 2 (2.4%) were Black or reported other, and 77 (90.3%) were White. Mean (SD) Montgomery-Åsberg Depression Rating Scale total scores improved from 25.6 (4.0) to 17.3 (8.9) for rTMS and 25.7 (4.7) to 15.8 (9.1) for TBS (adjusted difference, 1.55; lower 95% CI -0.67), establishing noninferiority for TBS. The all-cause dropout rates were relatively similar between groups (rTMS: 2 of 87 [2.3%]; TBS: 6 of 85 [7.1%]; P = .14; χ2 = 2.2).In older adults with TRD, bilateral TBS compared with standard bilateral rTMS achieved noninferior reduction in depression symptoms. Both treatments had low and similar dropout rates. Using TBS rather than rTMS could increase access to treatment several-fold for older adults with TRD.ClinicalTrials.gov Identifier: NCT02998580.
Biobehavioral Changes Following Transition to Automated Insulin Delivery: A Large Real-life Database Analysis
Authors: Boris P. Kovatchev, Harsimran Singh, Lars Mueller, Linda A. Gonder-Frederick
Journal: Diabetes Care (2022)

To document glycemic and user-initiated bolus changes following transition from predictive low glucose suspend (PLGS) system to automated insulin delivery (AID) system during real-life use.We conducted analysis of 2,329,166 days (6,381 patient-years) of continuous glucose monitoring (CGM) and insulin therapy data for 19,354 individuals with type 1 Diabetes, during 1-month PLGS use (Basal-IQ technology) followed by 3-month AID use (Control-IQ technology). Baseline characteristics are as follows: 55.4% female, age (median/quartiles/range) 39/19-58/1-92 years, mean ± SD glucose management indicator (GMI) 7.5 ± 0.8. Primary outcome was time in target range (TIR) (70-180 mg/dL). Secondary outcomes included CGM-based glycemic control metrics and frequency of user-initiated boluses.Compared with PLGS, AID increased TIR on average from 58.4 to 70.5%. GMI and percent time above and below target range improved as well: from 7.5 to 7.1, 39.9 to 28.1%, and 1.66 to 1.46%, respectively; all P values <0.0001. Stratification of outcomes by age and baseline GMI revealed clinically significant differences. Glycemic improvements were most pronounced in those <18 years old (TIR improvement 14.0 percentage points) and those with baseline GMI >8.0 (TIR improvement 13.2 percentage points). User-initiated correction boluses decreased from 2.7 to 1.8 per day, while user-initiated meal boluses remained stable at 3.6 to 3.8 per day.Observed in real life of >19,000 individuals with type 1 diabetes, transitions from PLGS to AID resulted in improvement of all glycemic parameters, equivalent to improvements observed in randomized clinical trials, and reduced user-initiated boluses. However, glycemic and behavioral changes with AID use may differ greatly across different demographic and clinical groups.
Genetic and Environmental Contribution to the Co-Occurrence of Endocrine-Metabolic Disorders and Depression: A Nationwide Swedish Study of Siblings
Authors: Marica Leone, Ralf Kuja-Halkola, Amy Leval, Agnieszka Butwicka, Jakob Skov, Ruyue Zhang, Shengxin Liu, Henrik Larsson, Sarah E. Bergen
Journal: American Journal of Psychiatry (2022)

Depression is common in individuals with endocrine-metabolic disorders and vice versa, and a better understanding of the underlying factors contributing to the comorbidity of these disorders is needed. This study investigated the familial coaggregation of depression and endocrine-metabolic disorders and estimated the contribution of genetic and environmental factors to their co-occurrence.This population-based cohort study included 2.2 million individuals born in Sweden between 1973 and 1996, with follow-up through 2013. Participants were linked to their biological parents, allowing identification of full siblings, maternal half siblings, and paternal half siblings. Diagnoses of depression and endocrine-metabolic conditions were investigated, with the latter grouped into autoimmune disorders (autoimmune hypothyroidism, Graves' disease, and type 1 diabetes) and non-autoimmune disorders (type 2 diabetes, obesity, and polycystic ovary syndrome). Logistic regression and Cox regression were used to estimate the associations between endocrine-metabolic disorders and depression within the same individual and across siblings. Quantitative genetic modeling was performed to investigate the relative contribution of genetic and environmental influences.Individuals with endocrine-metabolic disorders had a significantly higher risk of depression, with odds ratios ranging from 1.43 (95% CI=1.30, 1.57) for Graves' disease to 3.48 (95% CI=3.25, 3.72) for type 2 diabetes. Increased risks extended to full and half siblings. These correlations were mainly explained by shared genetic influences for non-autoimmune conditions, and by nonshared environmental factors for autoimmune disorders, especially for type 1 diabetes.These findings provide phenotypic and etiological insights into the co-occurrence of depression and various endocrine-metabolic conditions, which could guide future research aiming at identifying pathophysiological mechanisms and intervention targets.
Error in Data in Study of Estimated Cost of Bringing a Drug to Market
Journal: JAMA (2022)

and Development Investment Needed to Bring a New Medicine to Market, 2009Market, -2018," ," published in the March 3, 2020, issue of JAMA, 1 was corrected to update data throughout the article.The data changes originated because of corrections to one of the studies used as a source for clinical trial success rates.In addition to updated data throughout the Original Investigation, accompanying Editorials and Letters necessitated corrections to data. 2-6These articles have been corrected online, and a letter of explanation appears in this issue. 7
Evaluation of Fracture Risk Among Patients With Type 2 Diabetes and Nonvalvular Atrial Fibrillation Receiving Different Oral Anticoagulants
Authors: David Tak Wai Lui, Eric Ho Man Tang, Ivan Chi Ho Au, Tingting Wu, Chi Ho Lee, Chun Ka Wong, Chloe Yu Yan Cheung, Carol Ho Yi Fong, Wing Sun Chow, Yu Cho Woo, Kathryn Choon Beng Tan, Karen Siu Ling Lam, Carlos King Ho Wong
Journal: Diabetes Care (2022)

Patients with type 2 diabetes are at higher risk for fracture risk because of attenuated bone turnover and impaired bone microarchitecture. The comparative effect of warfarin over non-vitamin K antagonist oral anticoagulants (NOACs) on incident fractures among patients with type 2 diabetes comorbid with atrial fibrillation (AF) remains to be elucidated.This was a retrospective, propensity score-weighted, population-based cohort study of adults with type 2 diabetes and AF who were started on warfarin or NOAC between 2005 and 2019 identified from an electronic database of the Hong Kong Hospital Authority. The primary outcome was a composite of major osteoporotic fractures (hip, clinical vertebral, proximal humerus, and wrist). Hazard ratios (HRs) were calculated using Cox proportional hazards regression models.A total of 15,770 patients with type 2 diabetes comorbid with AF were included (9,288 on NOAC, 6,482 on warfarin). During a median follow-up of 20 months, 551 patients (3.5%) sustained major osteoporotic fractures (201 [2.2%] in the NOAC group, 350 [5.4%] in the warfarin group). The adjusted cumulative incidence was lower among NOAC users than warfarin users (HR 0.80; 95% CI 0.64, 0.99; P = 0.044). Subgroup analyses showed consistent protective effects against major osteoporotic fractures among NOAC users across sex, age, HbA1c, duration of diabetes, and history of severe hypoglycemia compared with warfarin users.NOAC use was associated with a lower risk of major osteoporotic fractures than warfarin use among patients with type 2 diabetes comorbid with AF. NOAC may be the preferred anticoagulant from the perspective of bone health.
Bacterial Toxin‐Responsive Biomimetic Nanobubbles for Precision Photodynamic Therapy against Bacterial Infections (Adv. Healthcare Mater. 18/2022)
Authors: Deli Zhuge, Li Li, Haonan Wang, Xuewei Yang, Dongyan Tian, Qingqing Yin, Hao Chen, Cuiye Weng, Bin Wen, Yijing Lin, Joo Young Huh, Xufei Zhang, Mengchun Chen, Congying Xie, Yingzheng Zhao, Yijie Chen
Journal: Advanced Healthcare Materials (2022)

Bacterial Infections Secreted bacterial toxins such as pore-forming toxins (PFTs) are capable of governing the photodynamic therapy (PDT) effect of RBC(IR780)-PFC(O2) nanobubble for treatment of source bacterial infections. Leveraging this unique approach, Mengchun Chen, Congying Xie, Yingzheng Zhao, Yijie Chen, and co-workers in article 2200698 are able to transform what would normally be considered a negative aspect of bacterial infections (i.e., toxin secretion) into a positive aspect.
Determinants of disparities between perceived and physiological risk of falling among elderly people: cohort study
Authors: K. Delbaere, J. C. T. Close, H. Brodaty, P. Sachdev, S. R. Lord
Journal: BMJ (2010)

<b>Objectives</b> To gain an understanding of elderly people's fear of falling by exploring the prevalence and determinants of perceived and physiological fall risk and to understand the role of disparities in perceived and physiological risk in the cause of falls. <b>Design</b> Prospective cohort study. <b>Setting</b> Community sample drawn from eastern Sydney, Australia. <b>Participants</b> 500 men and women aged 70–90 years. <b>Main outcome measures</b> Baseline assessment of medical, physiological, and neuropsychological measures, with physiological fall risk estimated with the physiological profile assessment, and perceived fall risk estimated with the falls efficacy scale international. Participants were followed up monthly for falls over one year. <b>Results</b> Multivariate logistic regression analyses showed that perceived and physiological fall risk were both independent predictors of future falls. Classification tree analysis was used to split the sample into four groups (vigorous, anxious, stoic, and aware) based on the disparity between physiological and perceived risk of falling. Perceived fall risk was congruent with physiological fall risk in the vigorous (144 (29%)) and aware (202 (40%)) groups. The anxious group (54 (11%)) had a low physiological risk but high perceived fall risk, which was related to depressive symptoms (P=0.029), neurotic personality traits (P=0.026), and decreased executive functioning (P=0.010). The stoic group (100 (20%)) had a high physiological risk but low perceived fall risk, which was protective for falling and mediated through a positive outlook on life (P=0.001) and maintained physical activity and community participation (P=0.048). <b>Conclusion</b> Many elderly people underestimated or overestimated their risk of falling. Such disparities between perceived and physiological fall risk were primarily associated with psychological measures and strongly influenced the probability of falling. Measures of both physiological and perceived fall risk should be included in fall risk assessments to allow tailoring of interventions for preventing falls in elderly people.
Interleukin-6 and Cardiovascular and Kidney Outcomes in Patients With Type 2 Diabetes: New Insights From CANVAS
Authors: Akihiko Koshino, Meir Schechter, Taha Sen, Priya Vart, Brendon L. Neuen, Bruce Neal, Clare Arnott, Vlado Perkovic, Paul M. Ridker, Katherine R. Tuttle, Michael K. Hansen, Hiddo J.L. Heerspink
Journal: Diabetes Care (2022)

OBJECTIVE The inflammatory cytokine interleukin-6 (IL-6) is associated with cardiovascular (CV) and kidney outcomes in various populations. However, data in patients with type 2 diabetes are limited. We assessed the association of IL-6 with CV and kidney outcomes in the Canagliflozin Cardiovascular Assessment Study (CANVAS) and determined the effect of canagliflozin on IL-6. RESEARCH DESIGN AND METHODS Patients with type 2 diabetes at high CV risk were randomly assigned to canagliflozin or placebo. Plasma IL-6 was measured at baseline and years 1, 3, and 6. The composite CV outcome was nonfatal myocardial infarction, nonfatal stroke, or CV death; the composite kidney outcome was sustained ≥40% estimated glomerular filtration rate decline, end-stage kidney disease, or kidney-related death. Multivariable-adjusted Cox proportional hazards regression was used to estimate the associations between IL-6 and the outcomes. The effect of canagliflozin on IL-6 over time was assessed with a repeated-measures mixed-effects model. RESULTS The geometric mean IL-6 at baseline, available in 3,503 (80.2%) participants, was 1.7 pg/mL. Each doubling of baseline IL-6 was associated with 14% (95% CI 4, 24) and 21% (95% CI 1, 45) increased risk of CV and kidney outcomes, respectively. Over 6 years, IL-6 increased by 5.8% (95% CI 3.4, 8.3) in the placebo group. Canagliflozin modestly attenuated the IL-6 increase (absolute percentage difference vs. placebo 4.4% [95% CI 1.3, 9.9; P = 0.01]). At year 1, each 25% lower level of IL-6 compared with baseline was associated with 7% (95% CI 1, 22) and 14% (95% CI 5, 22) lower risks for the CV and kidney outcome, respectively. CONCLUSIONS In patients with type 2 diabetes at high CV risk, baseline IL-6 and its 1-year change were associated with CV and kidney outcomes. The effect of IL-6–lowering therapy on CV, kidney, and safety outcomes remains to be tested.
FGF21–Sirtuin 3 Axis Confers the Protective Effects of Exercise Against Diabetic Cardiomyopathy by Governing Mitochondrial Integrity
Authors: Leigang Jin, Leiluo Geng, Lei Ying, Lingling Shu, Kevin Ye, Ranyao Yang, Yan Liu, Yao Wang, Yin Cai, Xue Jiang, Qin Wang, Xingqun Yan, Boya Liao, Jie Liu, Fuyu Duan, Gary Sweeney, Connie Wai Hong Woo, Yu Wang, Zhengyuan Xia, Qizhou Lian, Aimin Xu
Journal: Circulation (2022)

Exercise is an effective nonpharmacological strategy to alleviate diabetic cardiomyopathy (DCM) through poorly defined mechanisms. FGF21 (fibroblast growth factor 21), a peptide hormone with pleiotropic benefits on cardiometabolic homeostasis, has been identified as an exercise responsive factor. This study aims to investigate whether FGF21 signaling mediates the benefits of exercise on DCM, and if so, to elucidate the underlying mechanisms. The global or hepatocyte-specific FGF21 knockout mice, cardiomyocyte-selective β-klotho (the obligatory co-receptor for FGF21) knockout mice, and their wild-type littermates were subjected to high-fat diet feeding and injection of streptozotocin to induce DCM, followed by a 6-week exercise intervention and assessment of cardiac functions. Cardiac mitochondrial structure and function were assessed by electron microscopy, enzymatic assays, and measurements of fatty acid oxidation and ATP production. Human induced pluripotent stem cell-derived cardiomyocytes were used to investigate the receptor and postreceptor signaling pathways conferring the protective effects of FGF21 against toxic lipids-induced mitochondrial dysfunction. Treadmill exercise markedly induced cardiac expression of β-klotho and significantly attenuated diabetes-induced cardiac dysfunction in wild-type mice, accompanied by reduced mitochondrial damage and increased activities of mitochondrial enzymes in hearts. However, such cardioprotective benefits of exercise were largely abrogated in mice with global or hepatocyte-selective ablation of FGF21, or cardiomyocyte-specific deletion of β-klotho. Mechanistically, exercise enhanced the cardiac actions of FGF21 to induce the expression of the mitochondrial deacetylase SIRT3 by AMPK-evoked phosphorylation of FOXO3, thereby reversing diabetes-induced hyperacetylation and functional impairments of a cluster of mitochondrial enzymes. FGF21 prevented toxic lipids-induced mitochondrial dysfunction and oxidative stress by induction of the AMPK/FOXO3/SIRT3 signaling axis in human induced pluripotent stem cell-derived cardiomyocytes. Adeno-associated virus-mediated restoration of cardiac SIRT3 expression was sufficient to restore the responsiveness of diabetic FGF21 knockout mice to exercise in amelioration of mitochondrial dysfunction and DCM. The FGF21-SIRT3 axis mediates the protective effects of exercise against DCM by preserving mitochondrial integrity and represents a potential therapeutic target for DCM. URL: https://www. gov; Unique identifier: NCT03240978.